Sixty-four affected patients with autosomal dominant cerebellar ataxia from 28 families with at least three consecutive generations were recruited from 496 individuals referred by the Chesapeake Chapter of the National Ataxia Foundation located in Montgomery County, Maryland. Six individuals from 3 families had the SCA1 mutation (11%), 22 individuals from 8 families had the SCA3 mutation (29%), and 36 individuals from 17 families had neither mutation (36%). The point prevalence in Montgomery County, Maryland is estimated to be 2 per 100,000 persons. The number of CAG repeats on chromosome 14q was highly polymorphic with 16 different normal alleles ranging between 14 and 33 repeat units. The lower expansion of the CAG repeat in all affected individuals ranged between 67 and 83 repeats. Several larger alleles containing greater than 200 repeats were visualized on VISIGEL TM. The identity of the higher alleles was confirmed as containing (CAG)n repeats by Southern blot hybridization with a (CAG)n repeat probe. Sequencing of the CAG repeat region in four expanded alleles demonstrated the presence of a polymorphism at codon 300. An unsteady gait was reported as the first or second symptom in 18 of 19 affected individuals followed by visual disturbances in 9 patients. Cranial nerve findings, tone, reflexes, peripheral signs and muscle strength varied with the severity of the illness. Dystonia and Parkinsonian signs were notably absent in all patients studied. A comparison of 30 quantitative MRI images in affected American individuals with SCA3 and 21 quantitative MRI images in affected American individuals with SCA1 compared with normal controls, indicated a predominant spinopontine atrophy in SCA3 and a severe cerebellar atrophy in SCA1. These molecular, radiologic and clinical findings suggest that SCA3 is allelic to Machado Joseph disease. Decreased levels of CSF HVA, with normal levels of CSF 5-HIAA were found in our patients with SCA1 and SCA3. The CSF ratio of HVA/5-HIAA was lower in patients with SCA3 when compared to patients with SCA1. These findings may explain the lack of a therapeutic response to pharmacological agents that alter serotonin metabolism in patients with ADA. The lack of Parkinsonian signs in our patients with SCA1 and SCA3 implies that striatal dopamine deficiency is not marked early in the course of ataxia but the direct relationship between CSF HVA levels and the midsagittal pontine area on MRI indicates that depletion of dopaminergic neurons does plays a role in the pathogenesis of these genetic disorders.